Several ultimate chemical carcinogens, including monoalkylating agents, aromatic amines, and tumor-inducing metals induce strong, presumably covalent bonds between biological macromolecules. Complexes between DNA and proteins; DNA and DNA; DNA and RNA; RNA and proteins; RNA and RNA were recently observed in our laboratory. No similar macromolecular complexes are observed either with non-carcinogenic chemicals or with non-ultimate carcinogens. The latter class of agents, however, can be activated by addition of microsomal fraction from mouse and rat livers. We intend to extend these observations by systematically studying other carcinogenic chemicals and to assess the degree to which the formation of such intermolecular bridges may be involved in malignant transformation in vivo. Toward this end, the nucleic acids alone and in various combination with other cellular macromolecules and isolated cell organelles will be exposed to chemical carcinogens under a variety of experimental conditions (pH, varying concentrations of mono- and divalent cations, temperature, etc). The formation of intermolecular complexes will be monitored by several independent techniques. In the second part of this study, cells in culture and intact animals will be treated with carcinogens and radiation and correlation will be sought between the neoplastic transformation on one hand and the formation of such complexes on the other. We expect that these studies will increase our understanding of the mechanisms leading to malignant transformation of animal cells. BIBLIOGRAPHIC REFERENCES: H. Kubinski and E. H. Szybalski: Intermolecular linking and fragmentation of DNA by Beta propiolactone, a monoalkylating carcinogen. Chem. -Biol. Interactions 10, 41-55, 1975. B. B. Baril and H. Kubinski: Proximity of deoxyadenylic-thymidylic acid clusters to origin of DNA replication in E. coli minus T15 cells. Nature 255, 252-253, 1975.